DESCRIPTION: (abstract verbatim) Oropharyngeal candidiasis is particularly prevalent in patients who are immunocompromised by disease or immunosuppressive treatment. Interestingly, even in immunocompromised patients invasive oral candidiasis is rare and seems to be associated with additional risk factors such as extreme neutropenia. One strategy for improving resistance to opportunistic pathogens is to define host cellular responses during the invasion process and enhance those responses that are relevant to defense mechanisms. Compelling experimental evidence suggests that the primary effector cell responsible for Candida clearance is the neutrophil. Neutrophils accumulate rapidly at the site of infection in the oral cavity and participate in the local control of Candida growth and invasion, yet very little is known about the host signals responsible for regulating these events. Several cytokines provide signals for neutrophil activation of antifungal functions, including interleukin-1 beta (IL-1b) and granulocyte macrophage colony stimulating factor (GM-CSF). In cases of T-helper cell depletion or inactivation, such as HIV disease or Cyclosporin A treatment, PMN are most likely potentiated in their anti-fungal function by stimulating cytokines derived from non-immune cell. Epithelial cells are capable of synthesizing IL-1b and GM-CSF and maybe one of the few defenses remaining under CD+ T cell-deficient conditions. The central hypothesis of this project is that cytokines such as IL-1b and GM-CSF are released by oral epithelial cells upon interaction with Candida and act as local stimulators of neutrophil anti-fungal functions. Using a human oral epithelial cell Candida albicans coculture model system the applicants will first determine whether this microorganism can trigger secretion of these potent neutrophil activating cytokines by oral epithelial cells. Once this goal is accomplished, mechanisms eliciting Candida-mediated cytokine responses will be explored. Finally, they will perform functional assays for these epithelial cell-derived cytokines as they relate to neutrophil activation of Candida phagocytosis and killing, using isolated neutrophils from healthy, HIV+ and Cyclosporine A-treated individuals. Given the fact that most fungal infections take place in an immunocompromised host, neutrophil priming by non-immune cell derived cytokines may be of paramount importance, not just in the initiation of a protective inflammatory response, but also in the prevention of fungal invasion into the deeper connective tissues of the oral mucosa. The studies proposed herein will be crucial in identifying oral epithelial cell-derived cytokines with the potential to prime neutrophil antifungal function in vitro. Identification of such cytokines may have future therapeutic applications in the treatment of oral candidiasis in the severely immunocompromised host.